Chronic Management of Idiopathic

Generalized epilepsies (IGE)

Hassan S.Hosny M.D.

Prof of Neurology, Cairo University

Sanaa 2009

Points of Discussion

• Prevalence compared to focal epilepsy

• Adult form

• Status epilepticus

• Drug of choice

• Drug trials of new AEDs

• Seizure types

• Misdiagnosis

IGE diagnosis

• Strict clinical & EEG criteria features proposed by the ILAE

(no contamination with 2ry generalized epilepsies

• Easy to diagnose if clinical & EEG data are available (History)

• Sometimes diagnosis is made late & retrospectively after the 1st GTC as in JME

• IGE encompasses different syndromes & a patient may shift from one phenotype to another

• Diagnosis of epilepsy can be made after a single seizure

• Follow up EEGs may reclassify patients as having IGE

(Benbadis 2005, Berkovic 1987, Janz 1989,Reutens 1995,

Briellmann 2001,Loiseau 1995)

Diagnosis & Treatment of the 1st Seizure

• W.G is a 30 year old banker who presented with the 1st

GTCS during a business lunch

• He was rushed to the hospital where an MRI brain & EEG were done. All investigations were normal

• His concern was about the risk of recurrent seizures espat work

• A two hour EEG recording was done aiming to classify his seizure as partial or generalized

IGE with the 1st Generalized Tonic Clonic

Seizure

2 hour recording in a 30 y old male with the 1st GTCS

Defining IGE

• Overall, there are more similarities than differences in

various types of IGE (often impossible, controversial &

not necessarily important

• Same seizure types (3 types)

• Similar EEG findings

• Evolution to one another

• Overlapping genetic origin (ie; family members express

different IGE syndrome)

Case 2

• M.A is a 15 year old male who had a GTC seizure in November 2006.

• MRI brain & routine EEG (20mins) were normal

• No medication was given

• Jan 2007 got another GTCS (versive Sz). EEG was normal

• Was put on a starting dose of OXC 600mg/day

• He came one month later for a routine follow up visit

Epidemiology of IGE

(225/2000 11% 1995-2006)

• Clinical criteria as seizure type, age of onset, personal& family background, evolution &EEG are indispensable for diagnosis

• Some epileptic syndromes are rare & are excluded as BNFS & BMEI

• Some time elapses between onset of myoclonic seizures & first medical visit

• General frequency between 15%-20%

• CAE between 1.5% & 12.1%

• JAE under diagnosed (phantom absence)

• JME 10.7% & 11.4%

(Jallon 2005,Berg 1999,Oka 1995,Wolf 1986,Obeid 1988)

Newly diagnosed patients in children Presentations at

diagnosis (Berg ,1999)

• 613 Children 0-15 y over 4 years

• Mean age 5.3 years

• 58.6 % localization related:

10% idiopathic, 31% symptomatic localization related, 17%cryptogenic localization related

• Primary generalized epilepsy 20%

12% Absence

• Generalized cryptogenic symptomatic epilepsies 8.5% ( 3.9% infantile spasms)

Long term prognosis of Seizures with onset in

childhood (3 decades) ( Sillanpaa 1998)

• 245 children (prospective ) mean age 4.3 years

• 28% idiopathic seizures, 22% cryptogenic seizures, 50% remote

symptomatic seizures

• At end of follow up, 220 patients ( 44 died ,39 were not Sz free ,33

remote symptomatic Sz)

• 112 (64%) of surviving patients were seizure free for at least 5

years including 83 (47%) on no AEDs

• Predicators of being seizure free were rapid response to therapy

and a diagnosis of idiopathic seizures

Classification & long-term outcome in

Idiopathic generalized epilepsies (IGE)(Camfield 2004)

• 140 IGE patients (1977-1985)

• 58% had CAE, 65% went into remission

• 9% had JAE, 60% went into remission

• 10% had JME, 15% went into remission

• 23% ‘’ IGE not otherwise defined’ children with tonic

clonic seizures

Management of IGE

• Making a diagnosis is critical (pseudo-intractability)

• What’s beneficial in focal epilepsy may be deleterious in IGE

• Efficacy of AEDs differ within the IE seizure types

• Usually optimistic prognostic implications

• Awareness that IGE is a childhood as well as an adult syndrome

• Possibility of discontinuation of medication

• Preparation for adult life (seizure precipitants, gender issues)

22 year old male with intractable seizures

• Age 17 years had his 1st GTC. Received a small dose of Valproate 600mg/day.

• Checking liver enzymes, discovered to have HCV

• VPA was stopped and switched to CBZ up to 1200mg.Seizures increased in frequency 4/month.Add on Lamotrigine 400mg with no success. Add on Topiramate 300mg/day no success

22 year old male with intractable seizures

22 year old male with intractable seizures

Aggravation of seizures or epilepsy syndrome

((Generalized seizures))

YesUnvericht-

Lundberg

YesYesLKS/CSWS

YesYesBECTS

YesYesYesYesYesYesLGS/MAE

YesYesJME

YesYesYesYesMyoclonic

seizures

YesYesYesYesYesAbsence

seizures

BDZTGBVGBGBPLTGPHTCBZSeizure/syndro

me

Do AEDs with one mechanism of action aggravate

seizures?

Na blockade or increase in GABA transmission!!

Many seizure types in SMEI, myoclonic jerks in many syndromes

Lamotrigine

MyoclonicGabapentin, pregabalin

Absence, myoclonicVigabatrin, tiagabine

Absence, myoclonic, atonic, (?) tonic

Carbamazepine,oxcarbazepine,phenytoin

Tonic ( i.v. use, Lennox-Gastaut syndrome and West syndrome)

Benzodiazepines

Absence, tonicBarbiturates

Seizures AggravatedAEDs

SMEI = severe myoclonic epilepsy of infancy; JME = juvenile myoclonic epilepsy

Choice of the 1st AED in IGE does affect the

response (Nicolson et al , 2004)

• 962 with IGE (mostly adults) comparing VPA,LTG,TPM

285 /549 52% VPA, Dose 1286mg

26 /156 16% LTG Dose 324mg

9 /26 34% TPM Dose 256

• VPA failure due to side effects switching to LTG 6/44 (13%) achieved remission (did not receive LTG before)

• VPA ineffective , none achieved remission

• Polytherapy VPA + LTG 10/83 12 % achieved remission

• LTG failure switch to VPA 3/6 remission

• Conclusion: with VPA failure, Switch to polytherapy

• ?? Use of LTG as polytherapy rather than monotherapy in IGE

S.M 19 year old girl. Seizures started age 8 years GTCS ,myoclonic

jerks (stimulus sensitive), followed by cognitive decline. Positive

consanguinity and a younger brother with a similar condition

46%

17%

15%

2%

20%

JME

JAE

CAE

GTCS

MAE

Distribution of IGEs among the study group N: 225

GENDER

Age of onset & Gender

11.114.7+ 4.1GTCS

11.414.4+ 5.4JME

11.511.4+ 3.9JAE

11.26.7+ 2.7CAE

MaleFemaleMean age of

onset

Different seizure types in IGE syndromes

N : 225

• Video EEG monitoring

(absence & myoclonic

jerks are not reported by

patient)

• Epidemiological studies

undercount absences &

myoclonic jerks and refer

to them as GTCS0

20

40

60

80

100

120

CAE JAE JME

GTC Myoclonus Absence

Photosensitivity in IGE

8%

92%

Photosensitive

not Photosensitive

15 females & 3 males

Seizure control in 225 IGE patients

86%

14%

Controlled

uncontrolled31%

69%

Monotherapy

Polytherapy

Adequacy of control of seizures

• JME patients who continue to have myoclonus, what is the risk of

more GTCS (Mild Myoclonic Jerks Clonazepam is enough??)

• A Child with CAE controlled on a small dose of AED, is that

sufficient to prevent GTCS

• A child with subclinical generalized spike-wave discharges, is it

warranted to increase the dose to suppress the EEG discharges

• Cognitive functions in IGE in children suggesting long term risk of

learning impairment even with a normal IQ & controlled seizures

(Henkin ,2005 )

Seizure control in 36 CAE & 48 JAE patients

18%

8%

8%

16%

50%

VPA ESX LTG Poly drug resis

11%

55%

17%

17%

VPA other mono

cont poly unconrolled

Considerations for discontinuation of AEDs

(CAE)

• Remission of CAE in 65% of patients in well defined

syndrome

• If monotherapy is successful for 1-2 years ,it is

reasonable to try to discontinue medication

• Look for the next seizure type, even undetected

infrequent absence (risk of relapse!)

• Role of the video EEG monitoring (Wirrel 1997)

JME patients N: 103

68%

15%

14%

3%

VPA

poly cont

poly uncon

other mono

IGE with GTCS only

• Occur during wakefulness & sleep

• Peak 16-17 years

• Incidence range from 0.9% ,10%, 15%, 62%

• In it’s pure form CBZ,OXZ PHT can be used

• Secondarily GTCS may contaminate the selected population

• Semiological studies showed that focal features are quiet

common in GTCS of IGE (unilateral jerks, automatisms with absence, version with GTCS)

(Gelisse 2004, Reutens 1995, Roger 1994, Niaz 1999)

Seizure control in IGE with GTCS N:34

50%

35%

3%

12%

VPA

cont poly

PHT

uncont

Adult onset IGE

• Onset in adults in 15%

• No clear age boundary where early IGE & late onset IGE starts

• Often taught that epilepsy in adults should be assumed to have focal epilepsy

• 13% & 28 % had adult onset IGE mean age 23 Years , 50% had an adult myoclonic epilepsy

• Behavioral disturbances anxiety & depression despite well control of seizures

(Janz ,1997 Cutting, 2001 Marini 2003)

Early onset versus late onset IGE

15%

85%

adult onset

early onset

59%

26%

15%

JME

JAE

GTCS

Mean age of onset 21+ 3.8

Co-existence of focal and generalized

epilepsies

• P A is 38 year old journalist female

• 1st seizure age 26 followed by 2 GTCS in 3 months

• Remained seizure free for 3 years. Age 33 years recurrent psychomotor seizures followed by GTC. 5seizures in 1 day. Controlled on Oxcarbazepine1200mg/day. Non-compliance results in clusters of seizures. MRI normal. EEG showing left temporal slow waves and slowing

• Age 38 years complaining of frequent myoclonic jerks

38 year old female with seizures

Dose of VPA & LTG

Drug levels???

• Dose of VPA when used in monotherapy was 700-800

mg, while Lamotrigine was 150 mg

• Dose of VPA when used in polytherapy was 1000mg ,

while Lamotrigine was 100 mg (Max for VPA 2000

&300mg for LTG)

• In a RCT, no difference in control of various seizure

types could be demonstrated between 1000& 2000mg of

VPA(Sundquist, 1999)

27 year old female with seizures

• Onset of seizures age 21 years GTC

• EEG consistent with generalized discharges

• No myoclonus or absence

• On VPA 500 and LTG 75 mg/day

• Concerned about pregnancy so she stopped VPA and

remained on LTG 75 mg/day

• Remained seizure free for 2 years

• Husband called his mother in law asking her to come

because her daughter is acting in a strange way

27 year old female with seizures

Status epilepticus in IGE

Is it any different from SE in partial complex

seizure

• Absence status epilepticus is the SE encountered

• 2 females and one male

• Probable cause:

16 y old female sudden stoppage of VPA

55 y old female seizure free for years

53 y old male who received Quinilones

Study of patients & epilepsy variables &their

relation to seizure control

• Age of onset

• Sex

• Family history

• Seizure types

• Status epilepticus

• Febrile seizures

• Photosensitivity

Defining Intractability in IGE

Once refractory, always refractory ??

• 2 year period as in partial epilepsy

• Which seizure type is refractory

• Response to the 1st AED (depends on drug of choice)

• Pseudo-intractability (ill-advised drugs)

• Appearance of new seizure types

• Co-existence of IGE & focal epilepsy (9/962 patients)

• Generalized EEG with focal discharges

(Andrew 2004, Kwan &Brodie 2001)

Clinical trials in IGE

• In partial seizures, we ignore etiology& anatomy focusing on final expression (partial Complex Seizure or 2ry GTCS)

• IGE incorporate more than one seizure type which are electro-clinically & probably molecularly distinct

• Drugs that control GTCS worsen absence!

• Absence is a component of several syndromes so should we do clinical trials focusing on one seizure type or on one syndrome with several seizure types

• Infrequent seizure occurrence prolong trials & decreases statistical power

• Lifelong treatment (knowledge of long term side effects of AEDs)

Clinical Trials in well defined Syndromes

• Hardly any data on relatively uncommon IGE

• Most reviewers suggest Valproate (class III evidence) little evidence from RCT

• JAE (VPA extrapolated experience from its efficacy in control of the component seizure type

• CAE: Double blind parallel trial VPA vs ESM equally effective in 80% (verifying seizure count was manual), LTG ‘’Enrichment design study

• Trials in Primary GTCS , TPM

• Recent trials of LEV appear to be impressive (duration of trial??)

(Suzuki 1972, Sato 1982, Frank 1999, Biton 1999, La Neve 2004)

Conclusions

• A majority of IGE still receive ill-advised drugs ,one of the reasons

for pseudo-intractability

• A drug efficacious in one type of seizure may be ineffective or

exaggerate another type of seizure

• Small dose of the appropriate drug is as good as a large dose

• VPA still has superior efficacy in all seizure types

• When VPA fails, a combination of VPA + Lamotrigine appears to be

the most effective

Conclusions

• IGE syndrome are probably lifelong with the exception of CAE

• Non-convulsive status epilepticus occurs particularly in patients with

JAE

• It is still uncertain how effective are the new AEDs in controlling

IGEs

Thank you